Combined immunodeficiencies (CIDs) comprise a heterogeneous group of monogenic disorders manifesting with lymphocyte defects, recurrent infections and dysregulated immune response. Recently, we and others have described clinical and molecular features of the combined immunodeficiency syndromes caused by IL21 or IL21R loss-of-function mutations in humans. To date, only one homozygous mutation in the IL21 and five distinct homozygous mutations in the IL21R gene were identified, however only three have been published so far. 1, 2 Accordingly, comprehensive clinical and immunological data characterizing this novel type of CID are lacking. Here we report a novel homozygous frame-shift mutation in the IL21R gene of a patient presenting with T-, B-and natural killer (NK)-cell lymphopenia. The patient had eosinophilic duodenitis, sclerosing cholangitis, tinea corporis and otitis media, but no increased frequency of respiratory infections, as described in other IL21R-deficient patients. 3 Thus, our report expands on the clinical and functional characteristics of the IL21R deficiency, which may aid early diagnosis leading to improved treatment options. The cytokine IL21 regulates T-and B-cell proliferation and activation, 4, 5 and promotes NK-cell cytotoxicity. 6 IL21 binds to the IL21R, primarily expressed by lymphocyte populations and other hematopoietic cells, but it can also be found on non-hematopoietic cells including fibroblasts, keratinocytes and intestinal epithelial cells. 7, 8 IL21R and the interleukin-2 receptor common gamma-chain (IL2RG) form a heterodimer complex which upon IL21 binding initiates downstream signaling by activating Janus kinase 1, 3 (JAK1, JAK3) and inducing signal transducer and activator of transcription 1, 3 and 5 (STAT1, STAT3, STAT5) phosphorylation. 9 In affected individuals, loss-of-function mutations in the IL21R gene led to defective B-cell differentiation, impaired T-cell cytokine production, and impaired NK-cell cytotoxicity. Clinically these patients were characterized by cryptosporidiosis associated with severe chronic cholangitis leading to liver failure and respiratory tract infections, typically seen in patients with CID. 2 Recently, another IL21R-deficient patient suffering from chronic respiratory tract infections, however without cryptosporidium-associated cholangitis, was identified. 2 We recently described an IL21-deficient patient who was also cryptosporidium-negative and had no signs of cholangitis, but presented with very early-onset inflammatory bowel disease (IBD) which masked underlying CID at early age. 1 Thus the diversity of clinical phenotypes of the IL21 signaling defects prompts for identification and analysis of further patients to ultimately improve therapy. Our patient is a 7-year old Turkish boy born to healthy first-degree consanguineous parents (Online Supplementary Figure S1A). His older sister, who had chronic diarrhea and abdominal distention, died at the age of five. The patient’s complaint of chronic diarrhea started at the age of six months. Endoscopic biopsy revealed villous atrophy and blunting in focal areas, minimal increase in intraepithelial lymphocytes, eosinophilic leukocyte infiltration in lamina propria, minimal edema and inflammation in stroma leading to the diagnosis of eosinophilic duodenitis. The patient was referred to our immunology department for an investigation of potential underlying immunodeficiency at four years of age. In addition to chronic diarrhea, he suffered from recurrent otitis media, tinea corporis, tooth abscesses and recurrent herpes labialis. Physical examination revealed failure to thrive [weight 11 kg (2.3 kg< 3 percentile); height 84 cm (12 cm< 3 …